Abstract
Stimulation of CD95 (APO-1/Fas) by its natural ligand CD95L (APO-1L/FasL) leads to the formation of the death-inducing signaling complex. Here we report that upon CD95 stimulation in several T and B cell lines, a novel signaling complex is formed, which we term complex II. Complex II is composed of the death effector domain proteins as follows: procaspase-8a/b, three isoforms of c-FLIP (c-FLIP(L), c-FLIP(S), c-FLIP(R)), and FADD. Notably, complex II does not contain CD95. Based on our findings we suggest that CD95 signaling includes two steps. The first step involves formation of the death-inducing signaling complex at the cell membrane. The second step involves formation of the cytosolic death effector domain protein-containing complex that may play an important role in amplification of caspase activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / metabolism*
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Caspase 8 / metabolism
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Cell Membrane / metabolism
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Fas Ligand Protein / metabolism*
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Fas Ligand Protein / pharmacology
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Fas-Associated Death Domain Protein / metabolism
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Humans
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Jurkat Cells
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Mice
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Multiprotein Complexes / metabolism*
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Protein Isoforms / metabolism
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Protein Structure, Tertiary / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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T-Lymphocytes / metabolism*
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fas Receptor / agonists
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fas Receptor / metabolism*
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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FADD protein, human
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Fas Ligand Protein
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Fas-Associated Death Domain Protein
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Multiprotein Complexes
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Protein Isoforms
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fas Receptor
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Caspase 8